Matrix metalloproteinase 9 in pediatric rheumatic heart disease with and without heart failure
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BIOMEDICAL REPORTS 14: 4, 2021
Matrix metalloproteinase‑9 in pediatric rheumatic
heart disease with and without heart failure
AHMED A. ELHEWALA1, MOHAMMED SANAD1, ALSHIMAA M. SOLIMAN1,
MAY M. SAMI2 and ALSHYMAA A. AHMED2
Departments of 1Pediatrics, 2Clinical Pathology, Faculty of Medicine, Zagazig
University, Zagazig, Al Sharqia Governorate 44519, Egypt
Received July 7, 2020; Accepted September 30, 2020
DOI: 10.3892/br.2020.1380
Abstract. In cardiovascular disorders, the myocardium may detected HF with a sensitivity 95% (95% CI, 83.08‑99.39),
be subjected to the breakdown and remodeling of collagen specificity 74.14% (95% CI, 60.96‑84.74), positive predictive
by metalloproteinase‑9 (MMP‑9). We hypothesized that the value 71.70% (95% CI, 61.96‑79.75), negative predictive value
serum MMP‑9 concentration may be elevated in pediatric 95.56% (95% CI, 84.67‑98.82) and accuracy 82.65% (95% CI,
patients with rheumatic heart disease (RHD) and heart failure 73.69‑89.56). In addition, MMP‑9 showed a significant nega‑
(HF), and its level can be correlated with the HF severity. Thus, tive correlation with ejection fraction and fractional shortening
in the present study, we aimed to evaluate the sensitivity and (P=0.01 and P=0.02, respectively). In conclusion; MMP‑9 may
accuracy of MMP‑9 to predict HF in children with RHD and be an independent sensitive marker with which to detect HF in
to determine its effectiveness as an indicator of the degree of children with RHD and it can predict the prognoses of these
HF. This study included 98 consecutive children admitted to patients as it correlates with the severity of HF. Further studies
the Department of Pediatrics, Zagazig University Hospital, Al considering MMP‑9 in the detection of ‘silent’ RHD in school
Sharqia Governorate, Egypt with newly diagnosed RHD. Their aged children and asymptomatic HF in children with known
ages ranged from 8.5 to 16 years. Fifty‑eight children had RHD RHD especially in rural areas, are highly recommended.
without HF while 40 children were complicated with HF which
was diagnosed clinically and by echocardiography. A total of Introduction
44 healthy children were enrolled as a control group. MMP‑9
serum levels were estimated by enzyme‑linked immunosor‑ Heart failure (HF) is defined as an abnormal cardiac func‑
bent assay. The serum MMP‑9 concentration was higher in the tion and/or structure that lead to the inability of the heart to
RHD without HF and RHD with HF groups than this level noted deliver oxygen to the tissues at a rate that compensates for
in the control (P2 ELHEWALA et al: MMP-9 IN PEDIATRIC RHEUMATIC HEART DISEASE
targets (7). Similarly, noninvasive tools to monitor patients including dyspnea, orthopnea, lower limb edema, ascites, and
with HF before the occurrence of clinical deterioration are intolerance to exercise with left systolic dysfunction, which
also required (8). was defined as an ejection fraction (EF) ≤55% as estimated by
Matrix metalloproteinases (MMPs) are zinc‑dependent transthoracic echocardiography (13).
endopeptidases that belong to the metzincin superfamily.
MMPs have a key role in tissue remodeling in cardiovascular Data collection and clinical examination. All patients
diseases (CVDs). MMPs are a promising target of therapy, as reported their full medical histories, including history of
the administration of doxycycline ‘a tetracycline antibiotic that rheumatic fever, and underwent general and thorough cardiac
acts as a nonspecific MMP inhibitor’ in myocardial infarction examinations. Children with recurrent ARF were diagnosed
patients improved ischemia/perfusion injury. Further studies according to the revised Jones criteria 2015 (14).
on the implications of specific MMPs in different CVDs are
required to clarify their role in disease progression and to aid Ethical consideration. Ethical approval for this study was
the discovery of new therapeutic targets (9). obtained from Zagazig University Institutional Research
Gelatinases (MMP‑2 and MMP‑9) are the most frequently Board (ZU‑IRB) (approval no. 6005‑23‑6‑2019). Written
analyzed MMPs in HF. According to the majority of studies, informed consent was obtained from the parents of the chil‑
active myocardium remodeling is associated with increased dren included in the study. All procedures were performed
activity and concentrations of MMP‑2 and MMP‑9, which can according to the Declarations of Helsinki (https://www.who.
be useful markers to identify patients at risk for HF develop‑ int/bulletin/archives/79(4)373.pdf).
ment, and as indicators of patient outcome (10). In one study;
circulating MMP‑9, in contrast to MMP‑2, was the only Sample size calculation. The sample size was calculated by
predictor of late‑onset congestive HF (11). applying the Buderer N 1996 formula (15) at a 95% confidence
We hypothesized that the serum MMP‑9 concentration interval (CI), 95% power, 98% sensitivity and an expected
may be elevated in pediatric patients with RHD and HF, and its prevalence of 34% (16). An additional 10% was added to the
level can be correlated with the HF severity. Thus, the aim of calculated sample size to compensate for dropout.
the present study was to evaluate the sensitivity and accuracy
of the MMP‑9 level to predict HF development in children Methods
with RHD and to determine its effectiveness to indicate the Laboratory investigation. Complete blood counts were deter‑
degree of HF as detected by echocardiography. mined with Sysmex KX‑21 hematology analyzer (Sysmex
Corp.). C reactive protein (CRP) and antistreptolysin O (ASO)
Patients and methods levels were determined using automated nephelometry BN
Prospec (Siemens, UK) and turbidimeteric assay (Cobas 6,000,
Patients. This prospective study was conducted at the Pediatric Roche Diagnostics, Deutschland), respectively. The normal
Cardiology Unit, Pediatrics Department, Zagazig University range for CRP is up to 5 mg/dl, and that for ASO is up to
Hospital, Al Sharqia Governorate, Egypt, from September 200 IU/ml. Liver function tests and kidney function tests were
2015 to September 2019. The patients eligible for inclusion performed using Cobas Integra 400 Plus (Roche Diagnostics).
were consecutive children with age ≤16 years of either sex and All tests were performed at the Hematology and Chemistry
from the same Egyptian ethnicity. The patients were newly Units, Zagazig University Hospital Laboratories.
diagnosed with RHD by clinical presentation and echocar‑
diography based on the World Heart Federation criteria (12) Measurement of MMP‑9 serum levels. Plain tubes were
and whose parents agreed to provide written informed consent used to collect blood samples from patients when they were
for participation. Patients with underlying lung patholo‑ admitted to the hospital with suspected RHD. Sera were sepa‑
gies, bronchial asthma, congenital heart diseases (CHDs), rated and stored at ‑80˚C until analysis. MMP‑9 was analyzed
cardiomyopathy, aortic aneurisms, end organ failure, cancers, using a commercial MMP‑9 ELISA kit (Sunred Biological
or other complications of RHD such as atrial fibrillation, Technology), which applies the double antibody sandwich
pulmonary hypertension and thromboembolic disorders were ELISA technique (17) according to the manufacturer's guide‑
excluded from the study. lines. The laboratory staff was blinded to the clinical and
A total of 125 children with newly diagnosed RHD were echocardiography data of the patients.
enrolled in the study. However, 27 were excluded: 4 patients
had CHDs; 7 had lung disease according to X‑ray examina‑ Imaging techniques
tions; 9 had coexisting complications; 4 had increased serum Plain chest X‑ray in the postro‑anterior view. This imaging
creatinine levels; and 3 had inadequate serum samples. was performed to detect cardiomegaly and to exclude other
Ultimately, this study included 98 patients with a median age chest diseases.
(range) of 13.5 (8.5‑16) years. A total of 40 patients (43.2%)
had comorbid HF at presentation, while the remaining 58 Echocardiography. Conventional detailed echocardiography
(56.8%) had RHD without HF. The control group included 44 was performed in the Cardiology Unit of the Department of
healthy, age‑ and sex‑matched children. Pediatrics, Zagazig University Hospital. Ventricular systolic
function assessment, chamber dimensions, wall thickness,
Patient groups. Patients were categorized into two groups: left atrial diameter, left ventricular end diastolic diameter, left
RHD without HF and RHD with HF. This categorization was ventricular end systolic diameter, fractional shortening (FS),
based on the presence of clinical symptoms and signs of HF, and EF were all measured using M‑mode echocardiography.BIOMEDICAL REPORTS 14: 4, 2021 3
Pulsed or continuous wave Doppler ultrasound was used to Table I. Demographic characteristics of the patient groups.
assess the pressure gradient across the stenotic or regurgitated
flow through the valves as previously described (18). RHD without HF RHD with HF
Variable [n=58 (56.8%)] [n=40 (43.2%)] P‑value
Classification of patients with HF. Based on the EF, patients
were classified as mild HF, EF 40‑54%; moderate HF, 30‑39%; Age (year) 0.30
or severe HF, EF4 ELHEWALA et al: MMP-9 IN PEDIATRIC RHEUMATIC HEART DISEASE
Table II. Univariate and multivariate analyses of the predictors of heart failure.
Univariate analysisb Multivariate analysisc
‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
Factorsa OR 95% CI P‑value OR 95% CI P‑value
Hb ≥11.8 0.3 0.13‑0.73 0.008 0.3 0.1‑0.9 0.05
TLC ≥13.2 3.2 1.4‑7.5 0.006 3.3 1.3‑8.6 0.01
ASO ≥178.5 3.1 1.3‑7.3 0.008 3.1 1.2‑7.9 0.02
MMP‑9 ≥383.3 3.2 1.3‑7.3 0.008 2.6 1.0‑6.7 0.04
a
All numerical variables were dichotomized based on the median levels in patients except for MMP‑9 which was dichotomized based on the
mean value. bUnivariate analysis included all variables that showed significant differences among children with RHD without HF and children
with RHD and HF. cMultivariate analysis included all variable that were significant indicators in the univariate analysis. Significant P‑values
are shown in bold print. RHD, rheumatic heart diseases; HF, heart failure; Hb, hemoglobin; TLC, total leukocyte count; ASO, antistreptolysin
O; MMP‑9, matrix metalloproteinase 9.
Figure 2. Scatter plot with line chart for the correlation between MMP‑9
and EF. MMP‑9 levels increased significantly with the deterioration of EF
in the RHD with HF group. MMP‑9 matrix metalloproteinase‑9; EF ejection
Figure 1. ROC curve for MMP‑9 in the detection of HF in RHD. Serum fraction; RHD, rheumatic heart disease; HF, heart failure.
MMP‑9 concentration as a significant predictor of HF in children with RHD.
Area under curve=0.85 (0.76‑0.94) at 95% CI. ROC, receiver operating char‑
acteristic curve; MMP‑9 matrix metalloproteinase‑9; RHD, rheumatic heart
disease; CI, confidence interval. age, when compared to the controls, and in a patient group of
30 years of failure occurs.BIOMEDICAL REPORTS 14: 4, 2021 5
In the present study, serum levels of MMP‑9 were nega‑ the authors have indicated they have no financial relationships
tively correlated with EF and fractional shortening (FS). relevant to this article to disclose.
These results were also demonstrated by Yan et al (29) who
reported that elevated MMP‑9 levels were connected with the Availability of data and materials
deterioration in left ventricular (LF) function. According to
Yoshihisa et al (30); reduced EF is an independent predictor of Data are available upon reasonable request from the
increased cardiac event rates. The authors stated that the initial corresponding author.
assessment of LVEF is important for deciding treatment and
predicting prognosis. Based on this; we assumed that the serum Authors' contributions
MMP‑9 level may be associated with the prognostic status of
patients. Radosinska et al (10) proposed that the MMP‑9 level The requirements for authorship have been met by all authors.
may not only be a useful marker to identify patients at risk for All authors contributed to the study conception and design.
HF development but also, it can serve as an indicator of patient The original idea was conceived by AAE and MS. AAE and
outcome. According to Kantor and Rusconi, the most chal‑ MS also revised the manuscript before the publication. AMS
lenging point in pediatric HF is the choice of treatments. This contributed to the patient selection, history taking, data collec‑
may be an additional value of biomarkers, which may guide tion and blood sample withdrawal; under the supervision of
decisions of how to manage and predict patient outcomes (27). AAE and MS. MMS contributed to the data analysis, manu‑
To the best of our knowledge; MMP‑9 has not been previ‑ script writing, and plagiarism checking. AAA contributed to
ously studied in pediatric patients with RHD either in or outside sample processing, results collection, data analysis, manuscript
Egypt, at the time of writing this manuscript. Therefore, this writing and submission for publication. All authors certify
study adds to our general understading regarding the contribu‑ that personally wrote at least 90% of the manuscript. Finally,
tion of MMP‑9 to the pathogenesis of RHD and HF in children the manuscript was read and approved by all the authors. All
and draws attention to a new marker and target of therapy for authors are responsible for the reported research.
these patients.
On limitation of the present study was that it was conducted Ethics approval and consent to participate
on symptomatic patients in a single center; the sample size was
also relatively small. Thus, further multicenter studies with Ethics approval for this study was obtained from Zagazig
larger cohorts involving other types of MMPs are required to University Institutional Research Board (ZU‑IRB) (approval
confirm these results. Future studies concerning MMP‑9 in no. 6005‑23‑6‑2019). All procedures were performed according
the screening of school‑aged children for subclinical RHD in to the Declaration of Helsinki. Signed informed consent was
comparison with echocardiography, and screening of children obtained from the parents of the involved children.
with known RHD for asymptomatic cardiac dysfunction to allow
early and effective intervention before the development of overt Patient consent for publication
HF are highly recommended. Further investigations including
the correlation of MMPs with other cardiac biomarkers such as Not applicable.
natriuretic peptides (atrial or brain subtypes) or high sensitivity
CRP, the severity of symptoms and valve lesions, prospective Competing interests
follow‑up of children with HF to study the correlation between
MMPs and the degree of deterioration in cardiac function to All the authors have no competing interest to declare.
examine their role in monitoring these patients, and clinical
trials to investigate the effects of doxycycline in children Authors' information
suffering from RHD and HF are also recommended.
In conclusion, the MMP‑9 serum level can be considered Alshymaa A. Ahmed: ORCID ID: 0000‑0002‑8695‑4037.
as an independent sensitive indicator with which to identify
children with RHD who are at risk of HF events. MMP‑9 can References
be used to assess patients with HF; increased levels may indi‑
cate the need to intensify patient medical therapy. MMP‑9 was
1. Chaturvedi V and Saxena A: Heart failure in children:
higher in children with RHD either with or without HF than in Clinical aspect and management. Indian J Pediatr 76: 195‑205, 2009.
healthy controls; therefore, MMP‑9 is a promising diagnostic 2. Watkins DA, Johnson CO, Colquhoun SM, Karthikeyan G,
marker of subclinical RHD in school‑aged children, although Beaton A, Bukhman G, Forouzanfar MH, Longenecker CT,
Mayosi BM, Mensah GA, et al: Global, regional, and national
further studies are required. burden of rheumatic heart disease, 1990‑2015. N Engl J Med 377:
713‑722, 2017.
Acknowledgements 3. Dougherty S, Beaton A, Nascimento BR, Zühlke LJ, Khorsandi M
and Wilson N: Prevention and control of rheumatic heart disease:
Overcoming core challenges in resource‑poor environments.
Not applicable. Ann Pediatr Cardiol 11: 68‑78, 2018.
4. Carapetis JR, Beaton A, Cunningham MW, Guilherme L,
Funding Karthikeyan G, Mayosi BM, Sable C, Steer A, Wilson N,
Wyber R and Zühlke L: Acute rheumatic fever and rheumatic
heart disease. Nat Rev Dis Primers 2: 15084, 2016.
This research did not receive any specific grant from funding 5. Sorour KA: Rheumatic heart disease in Egypt: Gloomy past and
agencies in the public, commercial, or not‑for‑profit sectors. All promising future. Egypt Heart J 66: 139‑142, 2014.6 ELHEWALA et al: MMP-9 IN PEDIATRIC RHEUMATIC HEART DISEASE
6. Sarkar S, Rastogi M, Chaudhary P, Kumar R, Arora P, Sagar V, 21. Harfoosh AK, Elaziz AFA, Mahmoud E and Saleh A: Matrix
Sahni IS, Shethi S, Thakur K, Ailawadhi S, et al: Association of metalloproteinase‑9 as a potential biomarker for inflammatory
rheumatic fever & rheumatic heart disease with plausible early & events in acute coronary syndrome, and its relation to diabetes
late‑stage disease markers. Indian J Med Res 145: 758‑766, 2017. mellitus in these patients. Al‑Azhar Assiut Med J 13 (Suppl 1):
7. Fernandes BA, Maher KO and Deshpande SR: Cardiac S71‑S80, 2015.
biomarkers in pediatric heart disease: A state of art review. 22. Zhao Y, Zhou X, Liao X and Yang Z: Expression and significance
World J Cardiol 8: 719‑727, 2016. of matrix metalloproteinase‑1,9, tissue inhibitor of metallopro‑
8. Nadar SK and Shaikh MM: Biomarkers in routine heart failure teinase‑4 and extracellular matrix metalloproteinase inducer
clinical care. Card Fail Rev 5: 50‑56, 2019. in the myocardium of congestive heart failure in patients with
9. Azevedo A, Prado AF, Antonio RC, Issa JP and Gerlach RF: rheumatic heart diseases. Zhong Nan Da Xue Xue Bao Yi Xue
Matrix metalloproteinases are involved in cardiovascular Ban 34: 790‑795, 2009 (In Chinese).
diseases. Basic Clin Pharmacol Toxicol 115: 301‑314, 2014. 23. Abou‑Raya S, Naim A and Marzouk S: Cardiac matrix
10. Radosinska J, Barancik M and Vrbjar N: Heart failure and role of remodelling in congestive heart failure: The role of matrix metal‑
circulating MMP‑2 and MMP‑9. Panminerva Med 59: 241‑253, loproteinases. Clin Invest Med 27: 93‑100, 2004.
2017. 24. Collier P, Watson CJ, Voon V, Phelan D, Jan A, Mak G, Martos R,
11. Wagner DR, Delagardelle C, Ernens I, Rouy D, Vaillant M and Baugh JA, Ledwidge MT and McDonald KM: Can emerging
Beissel J: Matrix metalloproteinase‑9 is a marker of heart failure biomarkers of myocardial remodelling identify asymptomatic
after acute myocardial infarction. J Card Fail 12: 66‑72, 2006. hypertensive patients at risk for diastolic dysfunction and
12. Reményi B, Wilson N, Steer A, Ferreira B, Kado J, Kumar K, diastolic heart failure? Eur J Heart Fail 13: 1087‑1095, 2011.
Lawrenson J, Maguire G, Marijon E, Mirabel M, et al: World 25. Morishita T, Uzui H, Mitsuke Y, Amaya N, Kaseno K, Ishida K,
heart federation criteria for echocardiographic diagnosis of Fukuoka Y, Ikeda H, Tama N and Yamazaki T: Association
rheumatic heart disease‑an evidence‑based guideline. Nat Rev between matrix metalloproteinase‑9 and worsening heart failure
Cardiol 9: 297‑309, 2012. events in patients with chronic heart failure. ESC Heart Fail 4:
13. Jayaprasad N: Heart failure in children. Heart views 17: 92‑99, 321‑330, 2017.
2016. 26. Lee SD, Chen LM, Kuo WW, Shu WT, Kuo WH, Huang EJ,
14. Szczygielska I, Hernik E, Kołodziejczyk B, Gazda A, Tsai CC, Li PC, Liu JY, Chen TH and Huang CY: Serum
Maślińska M and Gietka P: Rheumatic fever‑new diagnostic insulin‑like growth factor‑axis and matrix metalloproteinases in
criteria. Reumatologia 56: 37‑41, 2018. patients with rheumatic arthritis or rheumatic heart disease. Clin
15. Juneja A and Sharma S: Issues of sample size in sensitivity and Chim Acta 367: 62‑68, 2006.
specificity analysis with special reference to oncology. J Cancer 27. Kantor PF and Rusconi P: Biomarkers in pediatric heart failure:
Res Ther 11: 482‑484, 2015. Their role in diagnosis and evaluating disease progression. Prog
16. Dougherty S, Khorsandi M and Herbst P: Rheumatic heart Pediatr Cardiol 31: 53‑57, 2011.
disease screening: Current concepts and challenges. Ann Pediatr 28. de Couto G, Ouzounian M and Liu PP: Early detection of
Cardiol 10: 39‑49, 2017. myocardial dysfunction and heart failure. Nat Rev Cardiol 7:
17. Isik A, Gursul C, Peker K, Aydın M, Fırat D and Yılmaz İ: 334‑44, 2010.
Metalloproteinases and their inhibitors in patients with inguinal 29. Yan AT, Yan RT, Spinale FG, Afzal R, Gunasinghe HR,
hernia. World J Surg 41: 1259‑1266, 2017. Arnold M, Demers C, McKelvie RS and Liu PP: Plasma matrix
18. Koestenberger M, Friedberg MK, Nestaas E, Michel‑Behnke I metalloproteinase‑9 level is correlated with left ventricular
and Hansmann G: Transthoracic echocardiography in the volumes and ejection fraction in patients with heart failure.
evaluation of pediatric pulmonary hypertension and ventricular J Card Fail 12: 514‑519, 2006.
dysfunction. Pulm Circ 6: 15‑29, 2016. 30. Yoshihisa A, Sato Y, Kanno Y, Takiguchi M, Yokokawa T, Abe S,
19. Ross RD: The ross classification for heart failure in children Misaka T, Sato T, Oikawa M, Kobayashi A, et al: Prognostic
after 25 years: A review and an age‑stratified revision. Pediatr impacts of changes in left ventricular ejection fraction in heart
Cardiol 33: 1295‑1300, 2012. failure patients with preserved left ventricular ejection fraction.
20. Cimmino G, Ragni M, Cirillo P, Petrillo G, Loffredo F, Open Heart 7: e001112, 2020.
Chiariello M, Gresele P, Falcinelli E and Golino P: C‑reactive
protein induces expression of matrix metalloproteinase‑9: A
possible link between inflammation and plaque rupture. Int J
Cardiol 168: 981‑986, 2013.You can also read
